JAK inhibitor JTE-052 regulates contact hypersensitivity by downmodulating T cell activation and differentiation. Issue 3 (December 2016)

• Record Type: Journal Article
• Authors: Amano, Wataru; Nakajima, Saeko; Yamamoto, Yasuo; Tanimoto, Atsuo; Matsushita, Mutsuyoshi; Miyachi, Yoshiki; Kabashima, Kenji
• Is Part Of: Journal of dermatological science. Volume 84:Issue 3(2016:Dec.)
• Page Start: 258
• Page End: 265
• Publication Date: 2016-12
• Subjects: JAK-STAT -- Contact hypersensitivity -- Skin inflammation -- Cytokines -- Effector memory T cell; Dermatology -- Periodicals; Skin Diseases -- Periodicals; Dermatologie -- Périodiques; 616.5005
• DOI: 10.1016/j.jdermsci.2016.09.007
• Languages: English
• ISSNs: 0923-1811

Abstract

Highlights: Oral administration of JTE-052 attenuated CHS, but did not affect croton oil-induced ICD or migration of dendritic cells. JTE-052 potently inhibited T cell proliferation and activation by antigen presentation in vitro. JTE-052 attenuated skin inflammation in a sensitized-lymphocyte transfer model without suppressing T cell migration. Abstract: Background: Using JAK inhibitors to inhibit cytokine signaling is presumed to be a possible means of treating skin inflammatory disorders such as contact dermatitis. Objective: To clarify the action site of JAK inhibitors in skin inflammatory disorders. Methods: We analyzed the mechanism of action of the JAK inhibitor JTE-052 using murine skin inflammation models, including contact hypersensitivity (CHS) and irritant contact dermatitis. Cells isolated from ear tissue or lymph node (LN) were analyzed by flow cytometry. The amounts of cytokines in the culture medium were measured by ELISA or bead array system. Proliferation of LN cells was evaluated by measurement of tritiated thymidine incorporation. Results: Oral administration of JTE-052 during both sensitization and elicitation phase attenuated CHS, but did not affect croton oil-induced irritant contact dermatitis. JTE-052 potently inhibited T cell proliferation and activation by antigen presentation in vitro, and attenuated skin inflammation in a sensitized-lymphocyte transfer model without suppressing T cell migration. JTE-052 did not affect hapten-induced cutaneous dendritic cell migration into draining lymph nodes or their costimulatory molecule expressions. Conclusion: The JAK inhibitor JTE-052 exerts an inhibitory effect on antigen-specific T cell activation and subsequent inflammation in acquired skin immunity, such as CHS.